Circulating Myeloid-Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension

Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, CO 80045, USA.
Chest (Impact Factor: 7.48). 09/2011; 141(4):944-52. DOI: 10.1378/chest.11-0205
Source: PubMed

ABSTRACT Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in the lungs of humans and animals with PH, and we hypothesized that they would be increased in the blood of patients with PH compared with control subjects.
Twenty-six children with PH and 10 undergoing cardiac catheterization for arrhythmia ablation were studied. Five milliliters of fresh blood were analyzed using flow cytometry. Results were confirmed using magnetic bead sorting and immunofluorescence, while quantitative polymerase chain reaction and intracellular urea concentration assays were used as measures of MDSC arginase-1 activation.
Flow cytometry demonstrated enrichment of circulating MDSCs among patients with PH (n = 26; mean, 0.271 × 10(6) cells/mL ± 0.17; 1.86% of CD45(+) population ± 1.51) compared with control subjects (n = 10; mean, 0.176 × 10(6) cells/mL ± 0.05; 0.57% of CD45(+) population ± 0.29; P < .05). Higher numbers of circulating MDSCs correlated to increasing mean pulmonary artery pressure (r = 0.510, P < .05). Among patients with PH, female patients had a twofold increase in MDSCs compared with male patients. Immunofluorescence analysis confirmed the results of flow cytometry. Quantitative reverse transcription polymerase chain reaction assay results for arginase-1 and measurement of intracellular urea concentration revealed increased activity of MDSCs from patients with PH compared with control subjects.
Circulating activated MDSCs are significantly increased in children with PH compared with control subjects. Further investigation of these cells is warranted, and we speculate that they might play significant immunomodulatory roles in the disease pathogenesis of PH.

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Available from: David Dunbar Ivy, Sep 28, 2015
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    • "They found significant enrichment of circulating fibrocytes and a positive correlation (albeit weak) between PAP and age. With the knowledge of ongoing inflammation in PH in which the innate and adaptive immune systems have been implicated, Yeager et al. also examined myeloidderived suppressor cells (MDSCs) [37], a subpopulation of which (monocyte-derived dendritic cells) was suggested to be functionally impaired in IPAH. Circulating MDSCs have been shown to be increased in human and animal PH lung. "
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    ABSTRACT: Analysis of the human proteome has become increasingly sophisticated, and offers invaluable potential insight into the pathophysiology of human disease. The increasing standardization of methods, speed and sophistication of mass spectrometric analysis, availability of reliable antibodies and dissemination of information among the scientific community has allowed for exponential growth of our knowledge base. The continued effort to provide a molecular explanation for future medical applications based on biomarker discovery is epitomized by the outstanding efforts of the human proteome project, whose goal is to generate a map of the human proteome. However, proteomic analysis is underrepresented in pediatric illness; given the unique challenges of research in the pediatric population, proteomic analysis represents enormous untapped potential, especially in the further elucidation of the pathophysiology of rare diseases such as pulmonary hypertension (PH). In this article we will describe the unique challenge of pediatric research, the importance of alternative avenues such as proteomics for in depth analysis of pediatric pathobiology at the cellular level, the specific need for proteomic investigation of pediatric PH, the current status of PH proteomics and future directions.This article is protected by copyright. All rights reserved
    PROTEOMICS - CLINICAL APPLICATIONS 12/2014; 8(11-12). DOI:10.1002/prca.201400067 · 2.96 Impact Factor
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    • "These results provide evidence that analysis of circulating white blood cells by flow cytometric quantification and subsequent gene expression characterization represent potentially important blood tests that could be integratively applied to current diagnostic and prognostic workups in children with PAH. Indeed, elevations of subsets of monocytic cell subsets have been identified in children with PAH (93, 94). Such studies, if confirmed in additional cohorts, could be prospectively expanded and performed serially to establish correlations to inflammation, disease progression, and response to therapy. "
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    Frontiers in Pediatrics 02/2014; 2:7. DOI:10.3389/fped.2014.00007
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    • "Evidence of inflammation in the PAH population is supported by production of proinflammatory cytokines, including interleukins (IL) [5], [10], growth factors including platelet-derived growth factor [22]–[23], vascular endothelial growth factor [24], and chemokines. Further, progenitor cells, such as fibrocytes and myeloid derived suppressor cells, may contribute to the fibroproliferative changes that characterize pulmonary hypertensive vasculopathy [25]–[26]. Although these proteins are associated with different pathogenic mechanisms and have involvement of different tissues, their combined involvement eventually contributes to the development of PAH, including endothelial and vascular smooth muscle cell dysfunction and proliferation in pulmonary vasculature. "
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    PLoS ONE 11/2013; 8(11):e80235. DOI:10.1371/journal.pone.0080235 · 3.23 Impact Factor
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